Pin1 Contribution to Alzheimer’s Disease: Transcriptional and Epigenetic Mechanisms in Patients with Late-Onset Alzheimer’s Disease

Abstract

Background: Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer’s disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing. Objective: In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT). Methods: Gene and protein expression, promoter methylation, Ser¹⁶ phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT. Results: In LOAD subjects, there was a statistically significant reduction in Ser¹⁶ phosphorylation (–30%; p = 0.041) and promoter methylation (–8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018). Conclusion: The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms.

Peripheral Blood Mononuclear Cells as a Laboratory to Study Dementia in the Elderly

“…Interestingly, a depletion of the soluble form of Pin1 has been described in neurons from AD subjects [57, 65] and differences in Pin 1 molecular and biochemical parameters have been reported in PBMCs from late-onset AD (LOAD) compared with control subjects [66]. …”

“…In particular, in PBMCs from LOAD we observed a significant increase in Pin1 gene expression together with a significant decrease in gene promoter methylation [66]. …”

“…For instance, our group has investigated the role of DNA methylation in the PBMCS from LOAD subjects compared to controls and has demonstrated an altered Pin1 gene expression and promoter methylation [66], as detailed above, along with changes in fatty acid amide hydrolase (FAAH) and 5-lipoxygenases (5-LOX) genes (Faah EC 3.5.1.99 and Alox5 EC 1.13.11.34), proteins, and activity [114]. …”

Brain site-specific proteome changes in aging-related dementia

“…79, 80, 81, 82, 83 Aside from its post-translational modifications, the expression levels of histones are also important for cell cycle control. 84 Here, we show that the expression of HIST1H1E was increased in the AD Hp, whereas the expression of HIST1H1D was increased in the AD pCx but decreased in the AD Cb.…”

Pin1 Modulation in Physiological Status and Neurodegeneration. Any Contribution to the Pathogenesis of Type 3 Diabetes?

“…Indeed, Arosio and collaborators found upregulated Pin1 gene expression in PBMCs of late onset AD patients and significantly reduced percentage methylation of Pin1 gene promoter. In PBMCs of these patients, Pin1 quantity and activity tended to be reduced as well [86]. To explain this apparent divergent behavior, Wang [87] suggested that Pin1 reduction contributes first to the accumulation of hyperphosphorylated tau in AD patients, but successively Pin1 is over expressed to compensate for the increased formation of Aβ plaques.…”